The overall objective of the present Program Proposal is to improve our understanding of the pathophysiologic mechanism leading to hypoxic- ischemic damage in the human fetus and newborn infant and to develop effective strategies to prevent or minimize permanent brain injury which leads ultimately to mental retardation or developmental disability. Our specific aims include: 1) to investigate underlying biochemical mechanisms responsible for the occurrence of hypoxic-ischemic brain damage in perinatal animals; 2) to study the evolution of alterations in cerebral blood flow and metabolism which culminates in hypoxic-ischemia brain damage; 3) to study the efficacy and mechanisms of action of specific neuro-protective agents in preventing or reducing the severity of perinatal hypoxic-ischemic brain damage; and 4) to ascertain whether or not prolonged or repetitive seizure superimposed on cerebral hypoxia- ischemic causes or accentuates the ultimate brain damage. All experiments will be conducted in developing postnatal rats and newborn dogs. Included in the Program Project Proposal are five basic research projects and three Core projects, the latter two include an Administrative and Biostatistics Core, Neuropathology Core, and MR Spectroscopy and Imaging Core. The individual research project titles are: 1) Regional cerebral blood flow and oxidative metabolism; 2) Free radical formation; 3) Energy metabolism; 4) Hypothermic circulatory arrest; and 5) Status epilepticus. Analytical techniques to be utilized include isotopic autoradiography, spectrofluorometry, high pressure liquid chromatography, 31P MR spectroscopy, MR imaging, light and electron microscopy. Scientific disciplines represented in the Program Project are pediatric neurology, perinatology, neuroradiology, neuropathology, neurochemistry, computer science and biostatistics. It is anticipated that the findings derived from the described research endeavors will have direct relevance to preventive and therapeutic interventions necessary to reduce substantially the significance and severity of mental retardation and development disability in developing human infants and children.